Neuro-stem cell stimulation and growth enhancement with implantable nanodevice

ABSTRACT

A nanodevice includes an array of metal nanorods formed on a substrate. An electropolymerized electrical conductor is formed over tops of a portion of the nanorods to form a reservoir between the electropolymerized conductor and the substrate. The electropolymerized conductor includes pores that open or close responsively to electrical signals applied to the nanorods. A cell loading region is disposed in proximity of the reservoir, and the cell loading region is configured to receive stem cells. A neurotrophic dispensing material is loaded in the reservoir to be dispersed in accordance with open pores to affect growth of the stem cells when in vivo.

RELATED APPLICATION INFORMATION

This application is related to commonly assigned application Ser. No.15/602,363, filed on May 23, 2017 (Attorney Docket Number:YOR920170190US1 (163-1706)), incorporated herein by reference.

BACKGROUND Technical Field

The present invention generally relates to implantable nanodevices, andmore particularly to devices and methods to control molecularinteractions at a device electrode by releasing materials factor toaffect cell growth.

Description of the Related Art

Neuro-degenerative disease can be treated with neuro stem cells, but aneffective method of placing the stem cells in a proper location,stimulating their differentiation into functional nerve cells, andproviding materials for their healthy growth remains a problem.

SUMMARY

In accordance with an embodiment of the present invention, a nanodeviceincludes an array of metal nanorods formed on a substrate. Anelectropolymerized electrical conductor is formed over tops of a portionof the nanorods to form a reservoir between the electropolymerizedconductor and the substrate. The electropolymerized conductor includespores that open or close responsively to electrical signals applied tothe nanorods. A cell loading region is disposed in proximity of thereservoir, and the cell loading region is configured to receive stemcells. A neurotrophic dispensing material is loaded in the reservoir tobe dispersed in accordance with open pores to affect growth of the stemcells when in vivo.

Another nanodevice includes an array of metal nanorods formed on asubstrate, the array of metal nanorods being grouped into a first regionand a second region. The first region includes first nanorods such thatupon activation of the first nanorods an electric field consistent withpromoting stem cell growth is achieved. The second region includessecond nanorods configured to activate an electropolymerized electricalconductor formed over tops of the second nanorods to form a reservoirbetween the electropolymerized electrical conductor and the substrate.The electropolymerized electrical conductor includes pores that open orclose responsively to electrical signals applied to the second nanorodsto release a growth factor.

A method for growing or differentiating in vivo stem cells includesproviding a reservoir with a cell growth promoter, the reservoir beingformed between an electropolymerized electrical conductor and a metallayer on a nanodevice, the electropolymerized electrical conductorincluding pores that open or close responsively to electrical signalsapplied to first nanorods extending from the metal layer of ananodevice; providing at least one stem cell on second nanorods of thenanodevice; placing the nanodevice in vivo; electrically stimulatingcell growth or differentiation of the at least one stem cell on thesecond nanorods; and dispensing the growth factor through theelectropolymerized electrical conductor by applying a first voltage tothe first nanorods to affect further growth of the stem cells.

These and other features and advantages will become apparent from thefollowing detailed description of illustrative embodiments thereof,which is to be read in connection with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The following description will provide details of preferred embodimentswith reference to the following figures wherein:

FIG. 1 is a cross-sectional view showing a substrate having a metallayer, organic planarizing layer, hard mask layer and patterned resistformed thereon for forming nanorods in accordance with an embodiment ofthe present invention;

FIG. 2 is a cross-sectional view showing the substrate of FIG. 1 havingthe metal layer exposed by etching the organic planarizing layer inaccordance with the hard mask layer and the patterned resist for formingnanorods in accordance with an embodiment of the present invention;

FIG. 3 is a cross-sectional view showing the substrate of FIG. 2 havingnanorods plated, connecting to the metal layer and planarized to thehard mask layer in accordance with an embodiment of the presentinvention;

FIG. 4 is a cross-sectional view showing a new cross-section with threenanorods formed on a substrate in accordance with an embodiment of thepresent invention;

FIG. 5 is a cross-sectional view showing the substrate of FIG. 4 havingan atomic layer deposited coating formed on the metal layer and thenanorods in accordance with an embodiment of the present invention;

FIG. 6 is a cross-sectional view showing the substrate of FIG. 5 havinganother organic planarizing layer formed and a hardmask patternedthereon in accordance with an embodiment of the present invention;

FIG. 7 is a cross-sectional view showing the substrate of FIG. 6 havingthe organic planarizing layer recessed to expose coated nanorods inaccordance with the patterned hardmask in accordance with an embodimentof the present invention;

FIG. 8 is a cross-sectional view showing the substrate of FIG. 7 havingthe coating removed from the nanorods that was exposed by the recess andhaving the patterned hardmask removed in accordance with an embodimentof the present invention;

FIG. 9 is a cross-sectional view showing the substrate of FIG. 8 havingthe organic planarizing layer removed in accordance with an embodimentof the present invention;

FIG. 10 is a cross-sectional view showing the substrate of FIG. 9 havingan electropolymerized conductor formed on the exposed nanorods inaccordance with an embodiment of the present invention;

FIG. 11 is a cross-sectional view showing the substrate of FIG. 10having pores of the electropolymerized conductor opened to load adispensing material into a reservoir in accordance with an embodiment ofthe present invention;

FIG. 12 is a cross-sectional view showing the substrate of FIG. 11prepared for deployment in vivo with the dispensing material and cellsloaded on the device in accordance with an embodiment of the presentinvention;

FIG. 13 is a cross-sectional view showing the substrate of FIG. 12having the dispensing material deployed through open pores in theelectropolymerized conductor in accordance with an embodiment of thepresent invention;

FIG. 14 is a cross-sectional view showing the substrate of FIG. 13 withstem cells being grown in vivo in accordance with an embodiment of thepresent invention;

FIG. 15 is a plan schematic view showing a nanodevice having nanorodsand circuits integrated on a substrate in accordance with an embodimentof the present invention; and

FIG. 16 is a block/flow diagram showing methods for fabricating andusing a nanodevice in accordance with embodiments of the presentinvention.

DETAILED DESCRIPTION

In accordance with embodiments of the present invention, an implantablenano-device can be created to provide effective methods for placingcells (such as e.g., stem cells) in a proper location, stimulating theirdifferentiation into functional nerve cells, and providing materials fortheir healthy growth. The nano-devices can solve these problems bycreating structures for electrically functional nano-pillar electrodes(also referred to as electrodes or nanorods) across a portion of adevice substrate and creating structures for nano-reservoirs of growthfactor with electrically controlled release in adjacent portions of thedevice substrate.

In one embodiment, the nano-pillar electrodes or nano-electrodes can beseeded with neuro stem cells. The nanodevice can be implanted into adesired region of neural tissue. The growth of the stem cells can beactivated by electrical stimulation. Timed release of the growth factorcan be appropriately activated into growth regions from thenano-reservoirs on the nanodevice.

In one embodiment, the nanodevices employ electrodes for detection ofneural activity, such as voltage changes around active neurons orconcentration levels of neurotransmitters. The electrodes can be formedas nanorods. A cell growth promoting mechanism can be employed tostimulate cellular growth from portions of a sensor or neurosensor byapplying appropriate chemicals or growth promoters in specific regionsof the device.

It is to be understood that aspects of the present invention will bedescribed in terms of a given illustrative architecture; however, otherarchitectures, structures, substrate materials and process features andsteps can be varied within the scope of aspects of the presentinvention.

It will also be understood that when an element such as a layer, regionor substrate is referred to as being “on” or “over” another element, itcan be directly on the other element or intervening elements can also bepresent. In contrast, when an element is referred to as being “directlyon” or “directly over” another element, there are no interveningelements present. It will also be understood that when an element isreferred to as being “connected” or “coupled” to another element, it canbe directly connected or coupled to the other element or interveningelements can be present. In contrast, when an element is referred to asbeing “directly connected” or “directly coupled” to another element,there are no intervening elements present.

The present embodiments can include a design for an integrated circuitchip, which can be created in a graphical computer programming language,and stored in a computer storage medium (such as a disk, tape, physicalhard drive, or virtual hard drive such as in a storage access network).If the designer does not fabricate chips or the photolithographic masksused to fabricate chips, the designer can transmit the resulting designby physical means (e.g., by providing a copy of the storage mediumstoring the design) or electronically (e.g., through the Internet) tosuch entities, directly or indirectly. The stored design is thenconverted into the appropriate format (e.g., GDSII) for the fabricationof photolithographic masks, which typically include multiple copies ofthe chip design in question that are to be formed on a wafer. Thephotolithographic masks are utilized to define areas of the wafer(and/or the layers thereon) to be etched or otherwise processed.

Methods as described herein can be used in the fabrication of integratedcircuit chips. The resulting integrated circuit chips can be distributedby the fabricator in raw wafer form (that is, as a single wafer that hasmultiple unpackaged chips), as a bare die, or in a packaged form. In thelatter case, the chip is mounted in a single chip package (such as aplastic carrier, with leads that are affixed to a motherboard or otherhigher level carrier) or in a multichip package (such as a ceramiccarrier that has either or both surface interconnections or buriedinterconnections). In any case, the chip is then integrated with otherchips, discrete circuit elements, and/or other signal processing devicesas part of either (a) an intermediate product, such as a motherboard, or(b) an end product.

It should also be understood that material compounds will be describedin terms of listed elements, e.g., SiGe. These compounds includedifferent proportions of the elements within the compound, e.g., SiGeincludes Si_(x)Ge_(1-x) where x is less than or equal to 1, etc. Inaddition, other elements can be included in the compound and stillfunction in accordance with the present principles. The compounds withadditional elements will be referred to herein as alloys.

Reference in the specification to “one embodiment” or “an embodiment”,as well as other variations thereof, means that a particular feature,structure, characteristic, and so forth described in connection with theembodiment is included in at least one embodiment. Thus, the appearancesof the phrase “in one embodiment” or “in an embodiment”, as well anyother variations, appearing in various places throughout thespecification are not necessarily all referring to the same embodiment.

It is to be appreciated that the use of any of the following “/”,“and/or”, and “at least one of”, for example, in the cases of “A/B”, “Aand/or B” and “at least one of A and B”, is intended to encompass theselection of the first listed option (A) only, or the selection of thesecond listed option (B) only, or the selection of both options (A andB). As a further example, in the cases of “A, B, and/or C” and “at leastone of A, B, and C”, such phrasing is intended to encompass theselection of the first listed option (A) only, or the selection of thesecond listed option (B) only, or the selection of the third listedoption (C) only, or the selection of the first and the second listedoptions (A and B) only, or the selection of the first and third listedoptions (A and C) only, or the selection of the second and third listedoptions (B and C) only, or the selection of all three options (A and Band C). This can be extended, as readily apparent by one of ordinaryskill in this and related arts, for as many items listed.

The terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of exampleembodiments. As used herein, the singular forms “a,” “an” and “the” areintended to include the plural forms as well, unless the context clearlyindicates otherwise. It will be further understood that the terms“comprises,” “comprising,” “includes” and/or “including,” when usedherein, specify the presence of stated features, integers, steps,operations, elements and/or components, but do not preclude the presenceor addition of one or more other features, integers, steps, operations,elements, components and/or groups thereof.

Spatially relative terms, such as “beneath,” “below,” “lower,” “above,”“upper,” and the like, can be used herein for ease of description todescribe one element's or feature's relationship to another element(s)or feature(s) as illustrated in the FIGs. It will be understood that thespatially relative terms are intended to encompass differentorientations of the device in use or operation in addition to theorientation depicted in the FIGs. For example, if the device in theFIGs. is turned over, elements described as “below” or “beneath” otherelements or features would then be oriented “above” the other elementsor features. Thus, the term “below” can encompass both an orientation ofabove and below. The device can be otherwise oriented (rotated 90degrees or at other orientations), and the spatially relativedescriptors used herein can be interpreted accordingly. In addition, itwill also be understood that when a layer is referred to as being“between” two layers, it can be the only layer between the two layers,or one or more intervening layers can also be present.

It will be understood that, although the terms first, second, etc. canbe used herein to describe various elements, these elements should notbe limited by these terms. These terms are only used to distinguish oneelement from another element. Thus, a first element discussed belowcould be termed a second element without departing from the scope of thepresent concept.

Referring now to the drawings in which like numerals represent the sameor similar elements and initially to FIG. 1, a partially fabricatednanodevice 10 is shown in accordance with one embodiment. The device 10includes a substrate 12 having one or more layers formed thereon. Thesubstrate 12 can include any suitable substrate structure, e.g., a bulksemiconductor, a semiconductor-on-insulator (SOI) substrate, etc. In oneexample, the substrate 12 can include a silicon-containing material.Illustrative examples of Si-containing materials suitable for thesubstrate 12 can include, but are not limited to, Si, SiGe, SiGeC, SiCand multi-layers thereof. Although silicon is the predominantly usedsemiconductor material in wafer fabrication, alternative semiconductormaterials can be employed as additional layers, such as, but not limitedto, germanium, gallium arsenide, gallium nitride, silicon germanium,cadmium telluride, zinc selenide, etc.

Since the present embodiments provide a device that can work remotely,the device 10 can include a substrate having powered circuitry forcontrolling the functions of the device. In this way, the substrate 12can include control circuitry fabricated using known semiconductorprocessing techniques. Components can include transistors, metal lines,capacitors, logic gates or any other electronic components that permitthe control of the nanorods and other structures to be formed insubsequent steps. In one useful embodiment, bipolar junction transistors(BJT) can be employed in the circuitry formed in the substrate 12. BJTdevices can be employed to generate sub-nanosecond pulsing, as will bedescribed.

A metal layer 14 is deposited on the substrate 12 and can be employedwith other components formed in the substrate 12 (e.g., a metal layer).The metal layer 14 can include a conductive but relatively inert metal,such as, e.g., Pt, Au, Ag, Cu, Ir, Ru, Rh, Re, Os, Pd, and their oxides(e.g., IrO₂, RuOx, etc.), although other metals, metal oxides and theiralloys can be employed. The metal layer 14 can be formed by depositionusing a sputtering process, chemical vapor deposition (CVD) process,atomic layer deposition (ALD), a plating process or any other suitabledeposition process.

In one embodiment, an organic planarizing layer (OPL) 16 is formed onthe metal layer 14. The OPL 16 can be formed by a spin-on process orother deposition process. Other dielectric layers can also be employed.

An etch stop layer or hard mask 18 can be deposited over the OPL 16. Inone embodiment the etch stop layer 18 can include a metal, such as,e.g., Ti, Ta, etc. or a metallic compound such as, e.g., TiN, TaN, SiARC(a silicon containing organic ARC layer), TiARC (a titanium ARC), etc. Aresist layer 20 is formed on the etch stop layer or hard mask 18. Theresist layer 20 can be spun on. The resist layer 20 is patterned to formopenings 22 that will be employed to form nanorods as will be described.

Referring to FIG. 2, an etch process is performed to open up the etchstop layer 18. In one embodiment, a reactive ion etch (RIE) process canbe performed to expose the OPL 16 through the openings 22 and 23 (FIG.1). Then, a RIE is performed to etch through the OPL 16 to expose themetal layer 14 and form trenches 24 in accordance with the resist 20and/or the etch stop layer or hard mask 18. The trenches 24 providelocations for the formation of nanorods. The etch of OPL 16 should beminimized to maintain small critical dimensions (CDs) for the hole ortrench 24 to be plated.

Referring to FIG. 3, a metal deposition process is performed and caninclude a plating process, CVD, sputtering or the like. The metal of thedeposition process preferably includes a same metal as employed in metallayer 14. In one particularly useful embodiment, the metal of layer 14and the metal used in nanorods 26 can include, e.g., Pt, Au, Ag, Cu, Ir,Ru, Rh, Re, Os, Pd, and/or their oxides (e.g., IrO₂, RuOx, etc.),although other metals, metal oxides and their alloys can be employed.The nanorods 26 can be annealed with the OPL 16 present or with the OPL16 removed. If the hard mask 18 includes, e.g., Ti or TiN, the hard mask18 can be removed with hydrogen peroxide aqueous solution, or if it isTi oxide or TiARC, it can be removed with diluted HF, as wet etching issimpler and easier to control than planarization processes such as,e.g., a chemical mechanical polish (CMP). However, a planarizationprocess, such as, e.g., CMP, can be employed if other hard maskmaterials are employed. The hard mask 18 is removed down to the OPL 16.Then, the OPL 16 can be removed by a plasma strip, e.g., oxygen plasma,forming gas plasma, with a mild wet clean to remove residues.

Referring to FIG. 4, after the removal of the OPL 16 and the anneal ofthe nanorods 26, the nanorods 26 are ready for continued processing. Thenanorods 26 can be arranged in any configuration suitable for creating ananodevice, e.g., an array with uniform or non-uniform spacings, etc.for chemical sensors, neurological implants or other applications.

Referring to FIG. 5, a coating 28 is formed over the nanorods 26 andmetal layer 14. The coating 28 is formed using, e.g., ALD, which can beprocessed to prepare a protective membrane on the electrodes or nanorods26. The membrane can include a SiO₂ film although other materialsincluding organic dielectrics can be employed. In one embodiment, thecoating can be formed by mixing ALD with aluminum, silicon or othermaterials, which can be formed in multiple layers. Each cycle of the ALDprocess can deposit a layer with an oxidation process thereafter to forma respective oxide (e.g., SiO₂ or Al₂O₃). In useful examples, the ALDreagent for forming Al can include AlMe₃ while the reagent for formingthe SiO₂ can include (Me₂N)₃SiH (where Me is a methyl group). The ALDprocess can include a plurality of cycles to deposit a plurality oflayers. The plurality of layers can include a large number (e.g., two toseveral hundred). The plurality of layers form the coating 28, which canhave a total thickness of between about 2 nm to about 50 nm. While otherdimensions are contemplated, the coating 28 preferably includes ananoscale thickness.

Referring to FIG. 6, another OPL 30 is formed over the coating 28. TheOPL 30 can be spun-on although other formation processes can beemployed. Another hardmask 32 is formed on the OPL 30. The hardmask 32can include a metal, such as, e.g., Ti, Ta, etc. or a metallic compoundsuch as, e.g., TiN, TaN, etc. A resist (not shown) can be employed in alithographic patterning process to pattern the etch mask 32 and protecta portion of the etch mask 32 during an etch. The etch, e.g., RIE,removes the hardmask 32 from a region 34 to open the region 34 for agrowth factor reservoir to be formed.

Referring to FIG. 7, the OPL 30 is recessed in the region 34 to exposetops 36 of the coating 28 over the nanorods 26 in the region 34. Therecess process can include a RIE selective to the coating 28 and thehard mask 32.

Referring to FIG. 8, a wet etch process can be performed to wet etchcoating 28 from the nanorods 26 in the region 34. The wet etch caninclude, e.g., a diluted HF etch (DHF). Another wet etch can beperformed to remove the hard mask 32 (FIG. 7) selectively relative tothe nanorods 26 and the OPL 30. For example, if the hard mask 32includes Ti, a wet etch with hydrogen peroxide (H₂O₂) can be employed toremove the hardmask.

Referring to FIG. 9, the OPL 30 is stripped to expose the coating 28 onthe nanorods 26. The OPL 30 can be stripped using a plasma etch, suchas, e.g., an O₂ plasma etch or N₂/H₂ plasma etch. The nanorods 26 whichhad coating 28 removed by, e.g., a wet etch previously, are exposedwithin the region 34.

Referring to FIG. 10, an electropolymerization process is performed togrow an electrically conductive porous polymer 40 on the exposedportions of the nanorods 26 in the region 34. In one embodiment, theporous polymer 40 forms an electrically responsive nanoporous membranebased on polypyrrole doped with a dodecylbenzenesulfonate anion(PPy/DBS) that is electropolymerized on the nanorods 26.

Electropolymerization is the process by which a polymer is formed usingelectrical current. The electrical current can be provided through theexposed nanorods 26 in the presence of a polymer (e.g., polypyrrole insolution). Doping can occur in-situ or after formation with theabsorption of an anion or other charged molecule. The porous polymer 40includes a regular pore size. The porous polymer 40 is configured toprovide a large volume change depending on its electrochemical state,and the pore size can be actuated electrically. The porous polymer 40 isformed in its oxidation state. The porous polymer 40 includes athickness where pores formed therein include sufficient length to passthrough the entire porous polymer layer.

The coating 28 is then removed from remaining portions of the nanorods26 by a wet etch. The wet etch can include a diluted HF etch, althoughother etchants can be employed. Once formed, the porous polymer 40 canhave its pores opened or closed in accordance with an electricalpotential applied to the polymer 40 by nanorods 26.

The porous polymer 40 can include an electropolymerized electricalconductor that includes electrically conductive polymers, such as, e.g.,polypyrrole, polyanilines, poly(thiophene),poly(3,4-ethylenedioxythiophene), poly(p-phenylene sulfide),poly(p-phenylene vinylene), poly(acetylene) or combinations thereof.

Referring to FIG. 11, a reservoir 46 is formed between the polymer 40and the metal layer 14. The polymer 40 can be electrically actuated toopen pores 42 through the polymer 40, which switches to the polymermaterial's reduction state (as opposed to its oxidation state). Thestate changes can be made by a potential difference of between about 0.9to about 1.2 volts applied to the nanorods 26. When the pores 42 areopened, a growth inhibiter or growth factor 44 can be collected withinthe reservoir 46. The growth factor 44 can include any useful chemicalor reagent, e.g., a growth stimulator or promoter 44 can be loaded. Thegrowth factor 44 can include any useful chemical or reagent, e.g., aneurotrophic growth factor, hormone species (e.g., steroids, etc.),metabolic stimulants, other materials, or combinations.

A growth inhibiter (44) can be employed to inhibit further growth orslow the growth of the stem cells. The growth inhibitor 44 can includeany useful chemical or reagent, e.g., chemotherapy drugs (e.g.,cytotoxic agents, alkylating agents, anthracyclines, cytoskeletaldisruptors, epothilones, histone deacetylase inhibitors, peptideantibiotics, retinoids, etc.), hormone species (e.g., somatostatin,etc.), other materials, or combinations.

For example, the reservoir 46 can include neurotrophic growth factor orneurotrophins 48 that can include brain-derived neurotrophic factor(BDNF). BDNF is a protein that, in humans, is encoded by the BDNF gene.BDNF is a member of the neurotrophin family of growth factors, which arerelated to the canonical Nerve Growth Factor. Neurotrophic factors arefound in the brain and its periphery. BDNF acts on certain neurons ofthe central nervous system and the peripheral nervous system, helping tosupport the survival of existing neurons, and encourage the growth anddifferentiation of new neurons and synapses. Neurotrophins are proteinsthat help to stimulate and control neurogenesis, BDNF being one of themost active. Other examples of neurotrophins that can be employedinclude neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), and nerve growthfactor (NGF).

Once growth factor 44 is loaded, the pores 42 of polymer 40 are closedby changing the voltage on the nanorods 26.

Referring to FIG. 12, a nanodevice 50 can be placed in vivo by surgeryor injection. Prior to in vivo placement, neuro stem cells 47 are loadedinto a stimulation electrode region 35 of the device 50. The cells 47can be attached using electrical charge or using a gel or other media.The neuro stem cells 47 are loaded when the polymer 40 has closed pores42. The device 50 is then placed in vivo by a surgical procedure or byinjection into a host. The neuro stem cells 47 can be stimulatedelectrically to cause growth.

As cells 47 interact with the surface of the device 50, the cells 47 canbegin to grow to stimulate their differentiation into functional nervecells. The amount and type of electrical stimulation can vary dependingon the circumstances.

Referring to FIGS. 13 and 14, electrodes (nanorods 26) in region 34 areactivated to open the pores 42 of the polymer 40 to an open position.This permits growth factor 48 to be released through the pores 42. Thegrowth factor 48 includes a dosage that will provide additional growthstimulation to the stem cells 47. The growth factor 48 promotes thegrowth of the cell or cells 47 increasing the size of the cell 47 asdepicted in FIG. 14.

The opening of the pores 42 can be performed in a pulsatile (oron-demand) manner so that the release of growth factor 48 can becarefully controlled. A switching time of a few seconds or less can beemployed to provide local and on-demand delivery of the growth factor48. The pores 42 can be closed again by changing the voltage on thenanorods 26 in the polymer 40 until activated at a later time tostimulate cell growth or to treat a wound or other tissue.

Prior to placement of the device 50 in vivo, stem cells 47 are loaded ina cell loading region 54 of the device 50. The cell loading region 54can include exposed or coated electrodes 26. The cells 47 can be loadedusing a gel, liquid or other media to hold the cells in position duringtransport to a treatment area. The cells 47 can also be loaded using astatic electrical charge on the electrodes 26 in the cell loading region54. The device 50 can be placed in vivo to sense or measureconcentrations of materials within the body (e.g., using designatednanorods 26 or other sensors). The device 50 can be set or moved to aparticular location or locations within the body. The locations mayinclude locations where nerve tissue is missing, damaged or destroyed.

When cells 47 are needed to treat or replace nerve cells, the cells 47can be electrically stimulated to activate growth. During the growthcycle, reservoir 46, which is loaded with growth factor 44 (orinhibitor), can be selectively activated to release growth factormaterial to enhance or guide the growth of the cells 47. Inhibitor maybe employed to slow the growth, if needed. Electrodes (nanorods 26) inregion 34 are activated to open from the closed position depicted inFIG. 12 to release the growth factor 48. The growth factor 48 canstimulate growth including supporting the differentiation of stem cellsinto functional nerve cells.

It should be understood that the growth and differentiation of the stemcells 47 can be achieved by any combination of electrical pulses, growthfactors, inhibitors and other stimulants applied in any advantageoussequence or sequences. The nanorods 26 in region 54 can, for example,have a spacing, e.g., between about 30 nm-2000 nm, such that a commonvoltage applied to all nanorods 26 results in an electric field betweenthe nanorods. The electric field intensity can be controlled byadjusting voltage (e.g., between, e.g., about 0.01 volts to about 5volts. It should be understood that electric field intensity can beadjusted in a plurality of ways. For example, the size, shape anddensity of the nanorods 26 can be controlled. In other embodiments,pulse shapes and pulse frequencies can be adjusted and controlled forpulsations of voltage or current to the nanorods 26. Other electricfield intensity controls are also contemplated, e.g., nanorod coatings,such as, e.g., a porous protective coating, electrical insulatinglayers, etc. The voltage/electric field intensity can be controlledseparately in different regions (e.g., region 34 and region 54).

For example, region 54 can permit electrical stimulation of neuro-stemcells 47, in place on the device 50. Cell 47 can be bound to nanorodelectrodes 26 in region 54, which includes an electrical pulsation thatstimulates cell growth. The cells 64 can be employed in a treatmentprogram, e.g., in vivo. Growth stimulation can be provided in accordancewith the present embodiments depending on the electrical settings andenvironmental conditions created.

Referring to FIG. 15, a device 70 for promoting stem cell growth isillustratively shown in accordance with one embodiment. The device 70includes an array 72 of electrodes 80. The array 72 can include uniformspacings between electrodes 40; however, non-uniform spacings can alsobe employed. An illustrative encapsulation wall 27 is shown to form areservoir 46. A circuit 74 can include an array of transistors and/orother circuit components (e.g., integrated into the substrate 12)configured to activate or selectively activate electrodes. The circuit74 can be integrated into the substrate 12 using semiconductorprocessing techniques. The circuit 74 can include a power source, e.g.,if the device 70 is implantable in the body. Alternatively, the circuit74 can connect to a separate external power source.

The circuit 74 can be controlled using a controller circuit 76 thatgenerates signals to control which and in what manner electrodes 80 areactivated. The voltage can be programmed to activate the electrodes 80using a patterned metal layer 14 to connect to the electrodes 80 inlocalized areas to affect cell growth over specific regions of the array72 or the whole array 72. The activation of the electrodes can promotecell growth or selectively enable the release of growth factor indifferent regions of the device 70.

Device 70 can also include a biosensor that employs biologicalrecognition properties for selective detection of various analytes orbiomolecules. The biosensor 70 can generate a signal or signals thatquantitatively relate to a concentration of the analyte on or near theelectrodes 80. To achieve a quantitative signal, a recognition moleculeor combination of molecules can be immobilized at the electrodes 80,which convert the biological recognition event into a quantitativeresponse.

In some embodiments, the nanorod electrodes 80 can produce electricalfields for stimulating cell growth, releasing drugs or growth promotersor combinations of these tasks. The device 70 can oscillate betweenmeasuring cycles and cycles to promote cell growth. It should beunderstood that multiple reservoirs can be employed and separatelycontrolled having a same or different payloads, as needed.

Device 70 can include regions with different spacings between nanorods80 (e.g., region 88). Device 70 can include different cell growthpromoting mechanisms and can include electrical based systems usingspacings and electrical pulses to cause cell growth. The device 70 canbe made disposable after use. The substrate 12 and other components canbe coated or shielded to prevent contamination to the host frommaterials of the device 70.

In one embodiment, a cell loading region 90 (54, in FIG. 14) includescells 94 suspended in a media 92 to load the cells 94 on the device 70.The device can be covered or sheathed to protect the cells 94 and media92 during placement in vivo.

Referring to FIG. 16, methods for fabricating a cell growth promoting orstem cell differentiating nanodevice are illustratively shown anddescribed. In some alternative implementations, the functions noted inthe blocks may occur out of the order noted in the figures. For example,two blocks shown in succession may, in fact, be executed substantiallyconcurrently, or the blocks may sometimes be executed in the reverseorder, depending upon the functionality involved. It will also be notedthat each block of the block diagrams and/or flowchart illustration, andcombinations of blocks in the block diagrams and/or flowchartillustration, can be implemented by special purpose hardware-basedsystems that perform the specified functions or acts or carry outcombinations of special purpose hardware and computer instructions.

In block 102, nanorods are formed on a metal layer. The metal layer onwhich the nanorods are formed can be patterned to provide electricalconnections to the nanorods or groups of nanorods.

In block 104, the nanorods can be connected to a circuit to provideselective activation of the nanorods as electrodes. The circuit caninclude an integrated circuit formed within the same substrate as thenanorods are formed on. Alternately, the circuit or chip can connect orbe integrated with the substrate with the nanorods. Metal paths can beformed by patterning the metal layer on which the nanorods are formed.

In block 106, a conformal layer is formed over the nanorods by, e.g.,atomic layer deposition by depositing layers of aluminum or silicon andoxidizing. It should be understood that while Si and Al are preferredmaterials, other materials or combinations can be employed to form acoating or membrane.

In block 108, the conformal layer is recessed in at least one region(e.g., over a portion of the nanorods). This can include patterning ahardmask over a portion of the device and etching a protective layer,e.g., OPL, until tops of the coated nanorods are exposed. The exposedtops are etched to remove the coating and expose the nanorods. The hardmask and OPL or other protective material can then be removed.

In block 110, a polymer conductor is electropolymerized on tops ofnanorods (exposed by recessing) to form a reservoir between theelectropolymerized conductor and the metal layer. The electropolymerizedconductor includes pores that open and close responsively to electricalsignals applied to the nanorods. The electropolymerized conductor caninclude polypyrrole, which can be doped with anions to be formed in itsoxidation state.

In block 112, a cell growth affecting (promoting or inhibiting)dispensing material to be dispersed is loaded in the reservoir inaccordance with open pores. The reservoir can be formed using a metalboundary, a dielectric boundary or any other suitable material that canbe patterned in accordance with semiconductor formation processing. Thedispensing material can include neurotrophic materials, such as, e.g.,one or more neurotrophins. The pores are held open by applying anelectric field to the electropolymerized conductor (e.g., usingnanorods). The dispensing material is applied to the device and settlesthrough the open pores to load the reservoir.

In block 114, the pores are then closed for in vivo delivery andoperation using a voltage on the nanorods.

In block 116, cells, e.g., neuro-stem cells are provided or loaded ontonanorods in a cell loading region of the nanodevice. The cells areloaded using a media such as a gel or other liquid or can be held usinga static electrical charge.

In block 118, a removable protective sheath can be placed over thenanodevice to permit delivery to an in vivo location. The sheath can beremoved before nanodevice operation in vivo.

In block 120, the nanodevice is positioned in vivo or otherwise.

In block 122, an electrical charge is delivered and controlled tostimulate growth of the cells in vivo.

In block 124, the pores can be opened to dispense the dispensingmaterial in accordance with electrical signals. The electrical signalscan be pulsed to provide better control of an amount of dispensingmaterial released. The dispensing material can include a cell growthpromoter, drug, or other materials. In one embodiment, the dispensingmaterial can include a growth factor, such as, e.g., a neurotrophicgrowth factor, to stimulate the growth of stem cells, or other growthfactors, such as, e.g., hormones (e.g., steroids), cytokines, or otherproteins and stimulants.

The nanorods can be grouped into a first region and a second regionwhere the first region includes the electropolymerized conductor anddispenses material using electric fields on nanorods. A second regioncan include a cell growth region. The dispensing material can bedispersed two or more times by opening and closing the pores whenneeded.

In block 126, the cells are grown to differentiate the stem cells asnerve cells to replace missing or damaged nerve tissue.

Having described preferred embodiments for neuro-stem cell stimulationand growth enhancement with implantable nanodevices (which are intendedto be illustrative and not limiting), it is noted that modifications andvariations can be made by persons skilled in the art in light of theabove teachings. It is therefore to be understood that changes may bemade in the particular embodiments disclosed which are within the scopeof the invention as outlined by the appended claims. Having thusdescribed aspects of the invention, with the details and particularityrequired by the patent laws, what is claimed and desired protected byLetters Patent is set forth in the appended claims.

What is claimed is:
 1. A nanodevice, comprising: an array of metalnanorods formed on a substrate; a reservoir having pores that openresponsively to electrical signals applied to at least a portion of thenanorods; a cell loading region disposed adjacent to the reservoir, thecell loading region being configured to receive stem cells; and aneurotrophic dispensing material loaded in the reservoir to be dispersedin accordance with open pores to affect growth of the stem cells when invivo.
 2. The nanodevice as recited in claim 1, wherein the reservoirincludes electrically conductive polymers selected from the groupconsisting of polypyrrole, polyanilines, poly(thiophene),poly(3,4-ethylenedioxythiophene), poly(p-phenylene sulfide),poly(p-phenylene vinylene), poly(acetylene) and a combination thereof.3. The nanodevice as recited in claim 1, wherein the substrate includesa semiconductor material and further comprises a control circuit formedin the substrate to control activation of electrodes formed by thenanorods.
 4. The nanodevice as recited in claim 1, wherein theneurotrophic dispensing material includes a neurotrophin selected fromthe group consisting of brain-derived neurotrophic factor (BDNF),neurotrophin-3 (NT-3), neurotrophin-4 (NT-4) and nerve growth factor(NGF).
 5. The nanodevice as recited in claim 1, wherein the electricalsignals are pulsed to control an amount of neurotrophic dispensingmaterial released.
 6. A nanodevice, comprising: an electropolymerizedelectrical conductor formed over tops of at least a portion of an arrayof nanorods to form a reservoir between the electropolymerizedelectrical conductor and the substrate, the electropolymerizedelectrical conductor including pores that open or close responsively toelectrical signals applied to the nanorods; a cell loading regiondisposed adjacent to the reservoir; and a neurotrophic dispensingmaterial loaded in the reservoir to be dispersed in accordance with openpores to affect growth of cells when in vivo.
 7. The nanodevice asrecited in claim 6, wherein the electropolymerized electrical conductorincludes electrically conductive polymers selected from the groupconsisting of polypyrrole, polyanilines, poly(thiophene),poly(3,4-ethylenedioxythiophene), poly(p-phenylene sulfide),poly(p-phenylene vinylene), poly(acetylene) and a combination thereof.8. The nanodevice as recited in claim 6, wherein the array of nanorodsare formed on a substrate including a semiconductor material and furthercomprises a control circuit formed in the substrate to controlactivation of electrodes formed by the nanorods.
 9. The nanodevice asrecited in claim 6, wherein the neurotrophic dispensing materialincludes a neurotrophin selected from the group consisting ofbrain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3),neurotrophin-4 (NT-4) and nerve growth factor (NGF).
 10. The nanodeviceas recited in claim 6, wherein the electrical signals are pulsed tocontrol an amount of neurotrophic dispensing material released.
 11. Thenanodevice as recited in claim 6, wherein the cells include stem cells.12. A nanodevice, comprising: a reservoir having pores that openresponsively to electrical signals applied to at least one nanorod; acell loading region disposed adjacent to the reservoir; and aneurotrophic dispensing material loaded in the reservoir to be dispersedin accordance with open pores to affect growth of cells when in vivo.13. The nanodevice as recited in claim 12, wherein the reservoirincludes electrically conductive polymers selected from the groupconsisting of polypyrrole, polyanilines, poly(thiophene),poly(3,4-ethylenedioxythiophene), poly(p-phenylene sulfide),poly(p-phenylene vinylene), poly(acetylene) and a combination thereof.14. The nanodevice as recited in claim 12, wherein the at least onenanorod is formed on a substrate including a semiconductor material andfurther comprises a control circuit formed in the substrate to controlactivation of electrodes formed by the nanorods.
 15. The nanodevice asrecited in claim 12, wherein the neurotrophic dispensing materialincludes a neurotrophin selected from the group consisting ofbrain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3),neurotrophin-4 (NT-4) and nerve growth factor (NGF).
 16. The nanodeviceas recited in claim 12, wherein the electrical signals are pulsed tocontrol an amount of neurotrophic dispensing material released.
 17. Thenanodevice as recited in claim 12, wherein the at least one nanorod is aportion of an array of nanorods.
 18. The nanodevice as recited in claim12, wherein the cells include stem cells.